PhD defence
Elucidating DUX4-Mediated Molecular Mechanisms Underlying FSHD Pathophysiology Using Multi-Omics Approaches
- D. Zheng
- Date
- Friday 13 February 2026
- Time
- Location
-
Academy Building
Rapenburg 73
2311 GJ Leiden
Supervisor(s)
- Prof.dr.ir. S.M. van der Maarel
- dr. A. van den Heuvel
- dr. A. Mahfouz
Summary
Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease that causes progressive muscle weakness, mainly affecting the face, shoulders, and upper arms. The disease is triggered by the abnormal activation of a gene called DUX4, which normally functions only during the earliest stages of human development. When DUX4 becomes active in adult muscle cells, it disrupts normal muscle function and contributes to muscle damage.
In this research, I studied how DUX4 changes gene activity in muscle tissue and why its effects are unevenly distributed within the same muscle. Using advanced RNA sequencing technologies, I analysed gene activity at multiple levels, including individual cell nuclei, single muscle fibres, and detailed RNA variants. These approaches revealed that DUX4 is active in only a small fraction of muscle cells, but causes strong and harmful effects where it is expressed. Remarkably, DUX4 forces muscle cells to activate genetic programs that are normally only seen during early embryonic development.
I also analysed gene expression data from three-dimensional muscle models that more closely resemble human muscle tissue than traditional cell cultures. These models show clearer disease-related molecular changes and offer promising opportunities for future drug testing.
Overall, this work demonstrates that FSHD is a highly heterogeneous disease, with disease mechanisms operating locally and at different molecular levels. By improving our understanding of how DUX4 drives muscle damage, this research provides valuable insights that may support the development of more targeted and effective therapies for people living with FSHD.
PhD dissertations
Approximately one week after the defence, PhD dissertations by Leiden PhD students are available digitally through the Leiden Repository, that offers free access to these PhD dissertations. Please note that in some cases a dissertation may be under embargo temporarily and access to its full-text version will only be granted later.
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